SUBSTITUTED TETRAHYDRO-1H-PYRAZOLO{8 1,2-b{9 PHTHALAZINES

ABSTRACT

Substituted tetrahydro-1H-pyrazolo(1,2-b)phthalazine, e.g., 5-pchlorophenyl-2,3,4,10-tetrahydro-1H-pyrazolo(1,2-b)phthalazine, are prepared by the reduction of the corresponding phthalazinone or by ring closure of the corresponding 2-(3hydroxypropyl)phthalazine and are useful as central nervous system depressants.

United States Patent [15] 3,694,442 Houlihan 5] Sept. 26, 1972 [54] SUBSTITUTED TETRAHYDRO- IH- [56] References Cited PYRAZOLO[l,2-b]PHTHALAZINES UNITED STATES PATENTS [72] Inventor: William J. Houlihan, l5 Raynold Road, Mountain Lakes, 070 r 3,433,641 3/1969 Margot ..260/250 A [22] Filed: July 28, 1 Primary Examiner-Nicholas S. Rizzo 211 App] 5 9 7 Attorney-Gerald D. Sharkin, Frederick H. Weinfeldt, Robert S. Honor, Walter F Jewell and Richard E. Vila Related US. Application Data [57] ABSTRACT [63] Continuation-impart of Ser. No. 561,745, June Substituted tetrahydro-lH-pyrazolo[1,2- 30, 1966, Pat. No. 3,549,620. b]phthalazine, e.g., 5-p-chlorophenyl-2,3,4,l0-

tetrahydrol H-pyrazolo[ 1,2-b1phthalazine, are prepared by the reduction of the corresponding [52] US. Cl ..260/250 A; 260/239, 424/244 phthalazinone or by ring closure of the corresponding [51] Int. Cl. ..C07d 51/06 2-( 3-hydroxypropyl)phthalazine and are useful as central nervous system depressants.

Field of Search ..260/250 A I 19 Claims, No Drawings 1 SUBSTITUTED TETRAHYDRO- 1H- PYRAZOLO[ l ,2-B]PHTHALAZINES This application is a continuation-in-part of application Ser. No. 561,745, filed June 30, 1966 which has issued as US. Pat. No. 3,549,620 on Dec. 22, 1970.

The end compounds of the present invention may be represented structurally as follows:

preferably containing from one to four carbon atoms, e.g., methoxy, ethoxy, propoxy and butoxy; or R" together with either R or R form a methylenedioxy bridge; and

R" represents straight chain lower alkyl, preferably containing from one to four carbon atoms, e.g., methyl, ethyl, propyl and butyl; ally]; propargyl; or benzyl. As representative of the compounds of formula I encompassed within the scope of the present invention, there may be mentioned the following:

I ethyl, propyl and butyl; straight chain lower alkoxy,

derivative thereof to form the corresponding 2-(3- l -phenyl-4-cyclopentyl-6-ethyl-2,3 ,4,5 ,6,'7-hexahydrol l-l-2,6-benzodiazonine l-phenyl-6-ethyl-8-chloro-2,3,4,5,6,7-hexahydro l H- 2,6-benzodiazonine l-phenyl-6-benzyl-9-ethyl-2,3,4,5,6,7-hexahydro-1H- 2,6-benzodiazonine l -phenyl-6-methyl-8,9-dichloro-2,3,4,5,6,?-hexahydrol H-2,6-benzodiazonine l-phenyl-6,9-dimethyl-8-chloro-2,3 ,4,5 ,6,7-hexahydrol H-Z ,6-benzodiazonine l -phenyl-6-propargyll 0-methyl-2,3 ,4,5 ,6,7-hexahydro-lH-2,6-benzodiazonine l-phenyl-6-benzyl-8, l0-diethyl-2,3,4,5,6,7-hexahydro-lH-2,6-benzodiazonine l-p-chlorophenyl-6-methyl-2,3,4,5,6,7-hexahydrol H- 2,6-benzodi azonine l -p-chlorophenyl-6,8-dirnethyl-2,3,4,5 ,6,7-hexahydrolH-2,6-benzodiazonine l -p-methoxyphenyl-6-benzyl-2,3,4,5 ,6,7-hexahydro-' 1 H-2,6-benzodiazonine l-( 3-chlorophenyl )-6-allyl-2,3 ,4,5 ,6,7-hexahydro- 1H- 2 ,6-benzodiazonine l-( S-methoxypheriyl )-6-benzyl-2,3,,4,5 ,6,7-hexahydrol H-2,6-benzodiazonine l-p-tolyl-6-methyl-2,3,4,5 ,6,7-hexahydrol H-2,6-

benzodiazonine l-(3,S-dimethoxyphenyl)-4,6-diethyl-2,3,4,5,6,7-hex- I ahydrol H-2,6-benzodiazonine l-(p-fluorophenyl)-6-benzyl-2,3,4,5,6,7-hexahydrolH-2,6-benzodiazonine 1 l-(3,4-methylenedioxyphenyl)-6-methyl-2,3,4,5,6,7- hexahydrol H-2,6-benzodiazonine l-(4,5-methylenedioxyphenyl)-6-benzyl-2,3,4,5,6,7- hexahydrol H-2,6-benzodiazonine The compounds enumerated above as well as the other compounds encompassed by formula I may be prepared by reacting Z-benzoylbenzoic acid or an appropriately substituted derivative thereof with 3- hydrazinopropanol or an appropriately substituted hydroxypropyl)-4-phenyl-I-ZH-phthalazinone. The latter is then either converted (via halide synthesis) to the corresponding 2-(3-chloropropyl)derivative or l-phenyl-6-methyl-2,3,4,5,6,7-hexahydro-lH-2,6- reduced to form the corresponding 3-(3-hydroxbenzodiazonine ypropyl l-phenyl- 1 ,2,3,4-tetrahydrophthalazine. 1-ph nyl-4-m hy -6- y -2, ,7-hexahydro-1H- Either of the compounds thus obtained is then con- 2,6-benzodiazonine verted to the corresponding 2,3,5,l0-tetrahydro-1H- l-phenyl-4-cyclohexyl-6-allyl-2,3,4,5,6,7-hexahydropyrazolo[l,2-b]phthalazine which in turn is reacted lH-2,6-benzodiazonine with an appropriate halide to form the N -(subl-phenyl-4-methyl-6-propargyl-2,3,4,5,6,7-hexahydrostituted) halide salt thereof. The latter is then conlH-2,6-benzodiazonine verted to the corresponding 4,5,6,7-tetrahydro-3H-2,6- 1, -d p ylt y -l a y -Iii-2,6 benzodiazonine which is then reduced to form the benzodiazonine desired 2,3,4,5,6,7-hexahydrol H-2,6-benzodiazonine. 1-phenyl-4-ethyl-6-benzyl-2,3,4,5,6,7-hexahydro-lH- The above process may be represented structurally ,Zfi-WIK PQ EQsiQK .7 it asf l ow n R RV Riv --Rvi Riv Rvl NH2 :0 I NH R N-omonncmon cum-omon m 1 R ,1

c-on 1v" J Reduction Halide Synthesis Step2 Step3 (III) Ill" RV Riv Rvi Riv Rvi I I l 1 I w R t N--CH=CHRCHOH N-CHzCHRCHgCl 4 1 A!!! R!!! 6 Reduction Step 4\\ Step2 Rv RNA-Rd 1' V l R 10 N 1 /Haiide (R X Step5 VI R R R" I R\'i RH -Riv I l\ l R/ RI i i R Alkali Metal Alkoxidc RI R RII l a W} 1 H step 6 \V1;j m Rm t, vin

X- Reduction Step 7 In the above formulas, R, R, R", R', R, R, R and R are as above defined and X represents halogen having an atomic weight of at least 35, ie chlorine, bromine or iodine.

As illustrated above, Step 1 involves the reaction of a Z-bnnzoyl-benzoic acid with a 3-hydrazinopropanol to form the corresponding phthalazinone (ll). This reaction is conveniently carried out in the presence of an inert organic solvent and at elevated temperatures. However, neither the solvent nor temperature employed is critical. Suitable solvents include benzene, alkylbenzenes, such as toluene or xylene, and cycloalkanes, such as cyclohexane and cycloheptane.

Preferably, the reaction is carried out at reflux temperature to effect the continuous removal of water. To facilitate the formation of water, the reaction may be carried out in the presence of a catalytic amount of hydrogen ions such as by the use of an arylsulfonic acid, eg, benzenesulfonic acid, p-toluenesulfonic acid and the like. The resulting produce (ll) can be readily isolated employing conventional techniques.

The reduction (Step 2) of the phthalazinone (ll) or (IV) to the corresponding phthalazine (Ill) or (V), respectively, is readily carried out employing a hydride reducing agent, preferably an aluminum hydride, such as lithium aluminum hydride, butyl aluminum hydride,

triisobutyl aluminum hydride and the like. The reduction is conveniently effected in the presence of an inert organic solvent and at an elevated temperature, preferably reflux temperature. Suitable solvents which may be used include the ethers, such as diethyl ether and the like. However, neither the solvent nor temperature employed is critical. The resulting products.(III) or (V) are readily recovered in conventional manner. It should be noted that with respect to Step 2 involving the reduction of phthalazinone (IV) to the corresponding phthalazine (V) it was completely unexpected that reduction and simultaneous ring closure could beefct d nthismanne t.

Step 3 of the process involves the conversion of the 2-( 3-hydroxy-propyl)-phthalazinone (II) to 'the corresponding 2-(3-chloropropyl)-phthalazinone (IV). This is accomplished in standard manner employing any of the conventional agents used for this purpose. The preferred agent, however, is thionyl chloride. The reaction is conveniently carried out in any suitable inert organic solvent, such as, for example, benzene, an alkane, such as hexane and the like, and a haloalkane, such as dichloromethane, chloroform, carbon tetrachloride and the like. It is preferred to carry out the reaction at reflux temperature, but it can be carried out at room temperature-(20 C.) if desired. The resulting product (IV) can be readily recovered in conventional manner.

The conversion of the phthalazine (III) to the corresponding pyrazolo[ l,2-b]phthalazine (V), as indicated by Step 4 of the above reaction scheme, is effected employing-the same conditions as set forth for Step 3. This reaction provides via halide synthesis and spontaneous ring closure the phthalazine (V).

Steps 5 and 6 of the process involve the introduction of the substituent R into the ring system followed by the opening of the nitrogen-nitrogen bond in the ring. In Step 5 the phthalazine (V) is reacted with an appropriate halide to form the corresponding N -(R' halide salt thereof (VI). This reaction is conveniently carried out in the presence of a suitable inert organic solvent, such as, for example, an ether such as diethyl ether and the like, an alkane such as pentane, hexane and the like, and an alkyl benzene, such as toluene, xylene and the like. It is preferred to carry out the reaction at room temperature or below although elevated temperatures up to reflux temperature can be employed if desired. The resulting halide salt (VI), which is readily isolated employing conventional techniques, is then converted to the corresponding benzodiazonine (VII) by reacting the halide salt (V1) with an alkali metal alkoxide (Step 6). Suitable alkoxides include the lithium, potassium and sodium derivatives of lower aliphatic alcohols, such as, for example, lithium methoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and the like. The

reaction is conveniently carried out in a suitable inert organic solvent such as aliphatic alcohol, for example methanol, ethanol, propanol and the like, and at an elevated temperature, preferably reflux temperature. However, neither the solvent nor temperature employed is critical. It should be noted that the opening of the pyrazole ring by the reaction of the halide salt (VI) with the alkali metal alkoxide is indeed unusual. The resulting product (VII) can readily be recovered in conventional manner.

The last step of the process (Step 7), the benzodiazonine (VII), is converted to the desired product (I) by reduction. The reduction can be effected in the same manner as set forth for Step 2. Alternatively, the reduction can be carried out by conventional catalytic hydrogenation employing a suitable catalyst, such as,.for example, platinum and palladium. The product (I) is readily recovered employing wellknown techniques.

With respect to the various steps of the process discussed above, it is possible that the solvent employed therein can be dispensed with if any of the reactants employed are liquids at the temperature at which the reaction is conducted. In such instances an excess of such reactant can be used in lieu of the solvent.

Various of the reactants employed in Step I of the process are known and can be preparedas described in the literature. Such other compounds which are not specifically disclosed in the literature may be readily prepared from available materials by methods analogous to those described in the literature for the preparation of the known compounds.

All of the compounds of structural formulas I, III, V and VI have asymetric centers and therefore exist as optically active isomers. Similarly, certain of the compounds of formulas II, IV and VII (depending upon the substituents attached thereto) exist in optically active forms. Furthermore, those compounds of structural fonnulas I, V, VI and VII, wherein R is other than hydrogen, also exist as geometric isomers. Separation and recovery of the respective isomers (optical and/or geometric) may be readily accomplished employing conventional techniques and such isomers are included within the scope of this invention.

The end compounds of the present invention in their free base form (compounds of formula I) are useful because they possess pharmacological activity. In particular, such compounds are central nervous system stimulants and can be used as anti-depressants. The intermediate compounds of formula V (in their free base form) are also central nervous system stimulants and therefore useful as anti-depressants. For such usage the above compounds may be combined with a pharmaceutically acceptable carrier, and such other conventional adjuvants, as may be necessary, and administered orally in such forms as tablets, capsules, elixirs, suspensions or solutions, or parenterally in such forms as injectable solutions, suspensions or emulsions. Furthermore, the compounds may be similarly administered in the form of their non-toxic, pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base, are readily prepared in conventional manner by reacting the base with the appropriate acid and accordingly are included within the scope of the invention. Representative of such salts are the mineral acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts such as the succinate, benzoate, acetate, maleate, p-toluenesulfonate, benzenesulfonate and the like.

As noted above, the compounds of formulas I and V exist as isomers. In some cases greater pharmacological activity or other beneficial attribute may be found with respect to a particular isomer and in such instances ad- .ministration of such isomer may be preferred.

For the above use the dosage administered will, of course, vary depending on the compound employed and mode of administration. However, in general, satisfactory results are obtained when these compounds are administered at a daily dosage of about 0.35 milligram to about milligrams per kilogram of animal body weight. This daily dosage is preferably administered two to four times a day, or in sustained release form. For most large mammals such as primates, the total daily dosage is from about 25 milligrams to about 150 milligrams. Dosage forms suitable for internal use comprise from about milligrams to about'75 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

A representative formulation suitable forzoral administration is a tablet prepared by standard tabletting techniques and containing the following:

Ingredient Parts by Weight 5-p-chlor0phenyl-2,3 ,5 l O-tetrahydrol H- pyrazolo [l,2-b]phthalazine 50 (calculated as the free base) Tragacanth Lactose 39.5 Corn Starch 5 Talcum 3 Magnesium Stearate 0.5

EXAMPLE 1 2-( 3-hydroxypropyl )-4-p-chlorophenyl- 1 -2H- phthalazinone (ll EXAMPLE 2 Following the procedure of Example I and employing an equivalent amount of the reactants enumerated below in place of those employed therein, there are obtained the products set forth below.

Product Benzoic acid Hydrazinopropanol 2-benzoylbenzoic acid 2methyl-3-hydrazinopropanol J-hydruzinop ropunol acid hydrnlinopropzmol hydroxypropyl)-4- phenyl- 1 -2H- phthalazinone 5-chloro-2-benzoylbenzoic acid 3-hydraxinopropanol 7-chloro-2-(3-hydroxypropyl )-4- phenyll -2 H- phthalazinone fi-methyl-Z-benzoylbenzoic acid 4,6-dichloro-2-benzoyl benzoic acid 4,6-dimethyl-2-benzoylbenwic acid Z-(mchlorobenzoyl) benzoic acid 2-( p-methoxybenzoyl) bcnzoic acid 2-( 3,4-dichlorobenzoyl)-benzoic acid 2-( 3,4-dimethoxybenzoyl)-benzoic acid 2-( 3-chloro-p-toluoyl)-benzoic acid 2-(4,5-methylenedioxybenzoyl)benzoic acid 6-methyl-2-(3,4- methylenedioxybenzoyl)benzoic acid 2-( p-fluorobenmyl) benzoic acid 2-phenyl-3-hydrazinopropanol 3-hydrazinopropanol 3-hydrazinopropanol B-hydrazinopropanol 3-hydrazinopropanol 3-hydrazinopropan0l 2-phenyl-3-hydrazinopropanol B-hydrazinopropanol 3-hydrazinopropanol 3-hydrazinopropanol 3-hydrazinopropanol 3-hydrazinopropanol EXAMPLE 3 8-methyl-2-( Z-phenyI-B-hydroxypro pyl )-4-phenyl- I-ZH-phthalazinone 6,8-dichloro-2- (ll-hydroxypropyl) -4-phenyll -2H- phthalazinone 6,8-dimethyl-2-( 3- hydroxypropyltphenyl- 1 -2H- phthalazinone 2-( Z-hydroxypropyl)-4-( m-chlorophenyl)- 1 -2H- phthalazinone 2-( B-hydroxypropyl) -4-(p-methoxyphenyl) 1 -2H- phthalazinone 2-( 3hydroxypropyl) -4-(p-tolyl)- 1 -2H- phthalazinone 4-( 3,4-dichlort phenyl)-2-( 2-phenyl -3-hydroxypropyl l-2H-phthalazinone 4-( 3,4-dimethoxyphenyl)-2-( 3-hydroxypropyl.)- 1 -2H- phthalazinone 4-( 3-chloro-pt0lyl)-2-(3-hydr0- xypropyl)- 1 -2H- phthalazinone 2-( 3-hydroxypropyl) -4-(4,5methylenedioxyphenyl)- I-Zl-I-phthalazinone 2-( S-hydroxypropyl) -8-methyl-4-( 3,4- methylenedioxyphenyl l-2H- phthalazinone 4-( p-fluorophenyl) -2-( 3-hydroxypropyl)-1-2H-phtha- Iazinone.

2-( 3-chloropropyl )-4-p-chlorophenyl- 1 -2H- phthalazinone (IV) I-(CHzhCl To a flask equipped with a stirrer is added 15.8 g.

I (0.05 mole) of 2-( 3-hydroxypropyl)-4-p-chlorophenyll-2H-phthalazinone, 8.9 g. (5.4 ml.) of thionyl chloride and 250 ml. of chloroform and the mixture refluxed with stirring for 20 hours. The mixture is then treated with a cold aqueous solution of sodium bicarbonate and then washed with a saturated aqueous solution of sodium chloride. The chloroform layer is then dried with sodium sulfate, filtered and concentrated on a rotary evaporator. The resulting residue is crystallized from a mixture of methylene chloride and diethyl ether to yield 2-(3-chloropropyl)-4-p-chlorophenyl-l-2H- phthalazinonc, m.p. l08-l09 C.

EXAMPLE 4 Following the procedure of Example 3 and employing an equivalent amount of the products enumerated in Example 2 for the phthalazinone used in Example 3, there are obtained the products set forth below.

phthalazinone 2-( 3-chloropropyl )-4-phenyll -2H-phthalazinone 2-( 2-cyclopropyl-3-chloropropyl)-4-phenyl- 1 -2H- phthalazinone 7-chloro-2-( 3-chloropropyl)-4-phenyl- 1 -2H- phthalazinone I 8methyl-2-( 2-phenyl-3-chloropropyl )-4-phenyl- 1-21-1- EXAMPLE 5-p-chlorophenyl-2,3 ,5 1 O-tetrahydrol H- pyrazolo[ l ,2-b lphthalazine (V).

To a flask equipped with stirring apparatus, dropping funnel, gas inlet tube and Soxhlet tube containing 50.0 g. (0.15 mole) of 2-(3-chloropropyl)-4-p-chlorophenyl-l-2l-l-phthalazinone is added under a nitrogen atmosphere 7.2 g. (0.19 mole) of lithium aluminum hydride and 2,000 ml. of anhydrous diethyl ether. The contents of the flask are refluxed with stirring for 48 hours and then cooled in an ice bath. The cooled mixture is then treated with [4.4 ml. of 2N sodium hydroxide and 21.6 ml. of water, filtered and the filtrate concentrated on a rotary evaporator. The residue is crystallized from diethyl ether to obtain 5-pchlorophenyl-2,3,5, l O-tetrahydrol H-pyrazolo[ l ,2-b] phthalazine, m.p. l22l25 C.

The base is dissolved in anhydrous diethyl ether and the resulting solution cooled in an ice bath. Hydrogen chloride gas is then passed through the cooled solution and the solids which form filtered off and crystallized from a mixture of methylene chloride and diethyl ether -19.. to obtain 5-p-chlorophenyl-2,3,5 l O-tetrahydrol H- pyrazolo[l,2-b]phthalazine hydrochloride, m.p. l89-192 C.-

EXAMPLE 6 Following the procedure of Example 5 and employing an equivalent amount of the products enumerated in Example 4 in place of the phthalazinone employed in Example 5, there are obtained the phthalazines set forth below. 2-methyl-5-phenyl-2,3 ,5, 1 O-tetrahydrol H-pyrazolo[ l ,2-b1phthalazine 5-phenyl-2,3 ,5 l0-tetrahydro-1H-pyrazolo[ l ,2-b ]phthalazine 2-cyclopropy1-5-phenyl-2,3,5 l O-tetrahydro- 1 H- pyrazolo[ l,2-b]phthalazine 8-chloro-5-phenyl-2,3,5 IO-tetrahydro l H-pyrazolo[ l ,2-b]phthalazine 9-methyl-2,5-diphenyl-2,3,5 l O-tetrahydrol H- pyrazolo[ l ,2-b]phthalazine 7,9-dichloro-5-phenyl-2,3 ,5 ,1 O-tetrahydro; 1H- pyrazolo[ 1,2-b1phthalazine 7,9-dimethyl-5-phenyl-2,3 ,5, l O-tetrahydro- 1H- pyrazolo[ l,2-b]phthalazine 5-(m-chlorophenyl)-2,3 ,5, IO-tetrahydro- 1 H- pyrazolo[ l,2-b]phthalazine 5-(p-methoxyphenyl)-2,3 ,5 l O-tetrahydrol H- pyrazolo[ 1,2-b]phthalazine 5-( p-tolyl )-2,3 ,5, lO-tetrahydrol H-pyrazolo[ l ,2-b ]phthalazine 5-( 3,4-dichlorophenyl)-2-phenyl-2,3,5 1 O-tetrahydrolH-pyrazolo[ l ,2-b]phthalazine 5- 3,4-dimethoxyphenyl)-2,3 ,5 l O-tetrahydrol H- pyrazolo[ l,2-b]phthalazine 5 3-chloro-p-tolyl )-2,3 ,5 IO-tetrahydrol H-pyrazolo[ l ,2-blphthalazine 5-( 4,5-methylenedioxyphenyl)-2,3,5,IO-tetrahydrolH-pyrazolo[ l ,2-b1phthalazine 9-methyl-5-( 3 ,4-methylenedioxyphenyl)-2,3 ,5 l 0- tetrahydrol Hpyrazolo[ l ,2-b]-phthalazine.

5 -(p-fluorophenyl)-2,3,5, IO-tetrahydro- 1H- pyrazolo[ l ,2-b]phthalazine.

EXAMPLE 7 l-p-chlorophenyl-3'-( 3-hydroxypropyl l ,2,3 ,4- tetrahydrophthalazine (Ill).

To a flask equipped with a stirring apparatus, dropping funnel, inlet tube and Soxhlet tube containing g. (0.32 mole) of 2-( 3-hydroxypropyl)-4-pchlorophenyl-l-2H-phthalazinone is added under nitrogen atmosphere 84.5 g. (2.2 mole) of lithium aluminum hydride and 2,500 mi. of anhydrous diethyl ether. The contents of the flask are stirred and refluxed EXAMPLE 8 Following the procedure of example 7 and employing an equivalent amount of the products enumerated in Example 2 in place of the phthalazinone employed in Example 7, there are obtained the phthalazines set forth below. 3-(2-methy1-3-hydroxypropyl)- l -phenyl 1 ,2,3,4- tetrahydrophthalazine 3-( 3-hydroxypr0pyl)- l -phenyl- 1 ,2,3,4- tetrahydrophthalazine 3-( 2-cyclopropyl 3-hydroxypropyl l -phenyll ,2,3,4-' tetrahydrophthalazine 6-chloro3-(3-hydroxypropyl)-1-phenyl-l,2,3,4- tetrahydrophthalazine v -methyl-3-( 2-phenyl-3-hydroxypropyl)- l -phenyll,2,3,4-tetrahydrophthalazine 5 ,7-dichloro-3-( 3-hydroxypropyl)- l -phenyll ,2,3 ,4- tetrahydrophthalazine i 5 ,7-dimethyl-3-(3-hydroxypropyl)-1-phenyl-l ,2,3,4- tetrahydrophthalazine 3-( 3-hydroxypropyl)- l m-chlorophenyl 1 ,2,3,4- tetrahydrophthalazine 3-(3-hydroxypropyl)-1-(p-methoxyphenyl)-1,2,3,4- tetrahydrophthalazine 3-( 3-hydroxypropyl)-l-( p-tolyl)-l ,2,3,4- tetrahydrophthalazine l-( 3 ,4-dichlorophenyl )-3-( 2-phenyl-3-hydroxypropyl l ,2,3,4-tetrahydrophthalazine l-( 3 ,4-dimethoxyphenyl )-3-( 3-hydroxypropyl 1 ,2,3 ,4-tetrahydrophthalazine l-( 3-chloro-p-tolyl )-3-( 3-hydroxypropyl 1 ,2,3,4- tetrahydropthalazine 3-( 3-hydroxypropyl l 4,5-methylenedioxyphenyl)- l,2,3,4-tetrahydrophthalazine 3-( 3-hydroxpyropyl )-5-methyll 3 ,4-methylenedioxyphenyl )-l ,2,3 ,4-tetrahydrophthalazine 3-( 3-hydroxypropyl)- l -(p-fluorophenyl)- 1 ,2,3,4- tetrahydrophthalazine EXAMPLE 9 5-p-chlorophenyl-2,3,5 1 O-tetrahydro- 1 H- pyrazolo[ l,2-b]phthalazine (V, via Step 4).

To a flask equipped with a stirrer is added 6.0 g. (0.02 mole) of 1-p-chlorophenyl-3-(3-hydroxypropyl)- l,2,3,4-tetrahydrophthalazine, 2.4 ml. (0.0] mole) of thionyl chloride and ml. of chloroform and the mixture stirred and refluxed for 20 hours. The mixture is then treated with a cold aqueous solution of sodium bicarbonate and then washed with a saturated aqueous solution of sodium chloride. The chloroform layer is separated, dried with sodium sulfate, filtered and then concentrated on a rotary evaporater. The residue is crystallized from a mixture of diethyl ether-pentane to obtain 5-p-chlorophenyl-2,3 ,5, l O-tetrahydro- 1 PL pyrazolo[ l,2-b]phthalazine, m.p. l23-l 25 C.

EXAMPLE 10 N -methyliodide salt of 5-p-chlorophenyl-2,3,5 l 0- tetrahydro- 1 H-pyrazolo-[ l ,2-b]-phthalazine (VI) EXAMPLE 1 1 Following the procedure of Example 10 and employing an equivalent amount of the reactants enumerated below in place of those employed therein, there are obtained the products set forth below.

Phthalazine Halide Product 2-methyl-5-phenyl-2,3,5,l0- Allyl N -allyl bromide salt tetrahydro-ll-l-pyrazolo[ l,2-b] bromide of 2-methyl-5-phenyl phthalazine -2,3,5, 1 O-tetrahydrolH-pyrazolo[ l,2- b]-phthalazine 5-phenyl-2,3,5, IO-tetrahydro- Benzyl N -benzyl chloride lH-pyrazolo[ l,2-b]phthalazine chloride salt of 5-phenyl-2,

3,5,l0-tetrahydrolH-pyrazolo[ l,2-

b]phthalazine Z-cyclopropyl-S-phenyl-2,3,5, Methyl N -methyl iodide l0-tetrahydrol H-pyrazolo iodide salt of 2-cyclo propyl [l,2.-b]phthalazine -5-phenyl-2,3,5,l0-

tetrahydrol H- pyrazolol l ,2-b]- phthalazine 8-chloro-5-phenyl-2,3,5,l0 Benzyl N -benzyl bromide tetral H-pyrazolol l,2- bromide salt of 8-chloro-5- phthalazine phenyl-2,3,5,l0-

tetrahydrol H- pyrzazolol l,2-b]- phthalazine 9-methyl-2,5-diphenyl-2,3,5, Methyl N -methyl iodide lO-tetrahydrol H-pyrazolo iodide salt of 9-methyl-2,5- 1,2-b1-phthalazine diphenyl-2,3,5 ,10-

tetrahydrol H- pyrazolol i,2-b]- phthalazine 7,9-dichloro-5-phenyl-2,3,5, Propargyl N -propargyl brol0 -tetrahydro-lH-pyrazolo bromide mide salt of 7,9-dil l,2-b]-phthalazine chloro-S-phenyl-Z,

A mixture of 5.4 g. of l-p-chlorophenyl-6-methyl- 4,5,6,7-tetrahydro-3H-2,6-benzodiazonine, 0.60 g. of platinum oxide and 100 ml. of acetic acid (in a Paar hydrogenation bottle) is hydrogenated at 50 p.s.i.g. and room temperature for 12 hours. The catalyst is then filtered off and the solvent removed in vacuo. The residue is made basic with aqueous 2N sodium carbonate and extracted into chloroform. The chloroform extract is then dried with magnesium sulfate, filtered and the chloroform removed in vacuo. The resulting oily residue is dissolved in a mixture of dichloromethane and diethyl ether and the resulting solution treated with dry hydrogen chloride to yield 1- pchlorophenyl-6-methyl-2,3,4,5,6,7-hexahydro-1H- 2,6-benzodiazonine dihydrochloride, m.p. 200-204 C.

EXAMPLE 15 Following the procedure of Example 14 and employing an equivalent amount of the benzodiazonines enumerated in Example 13 in place of the benzodiazonine used in Example 14, there are obtained the products set forth below. 6-allyl-4-methyl-1-phenyl-2,3,4,5,6,7-hexahydro-1H- 2,6-benzodiazonine 6-benzyl- 1 -phenyl-2,3,4,5 ,6,7-hexahydrol H-2,6- benzodiazonine 4-cyclopropyl-6-methyl-1-phenyl-2,3 ,4,5 ,6,7-hexahydrol H-2,6-benzodiazonine 6-benzyl-9-chloro-1-phenyl-2,3,4,5,6,7-hexahydrol 1H-2,6-benzodiazonine 1,4-diphenyl-6,8-dimethyl-2,3,4,5 ,6,7-hexahydrol H- 2,6-benzodiazonine 8,10-dichloro-l-phenyl-6-propargyl-2,3,4,5,6,7-hexahydrol l-l-2,6-benzodiazonine 6-ally1-8, lO-dimethyl-1-phenyl-2,3,4,5,6,7-hexahydro- 1 H-2,6-benz odiazonine 1-(m-chlorophenyl)-6-methyl-2,3,4,S,6,7-hexahydroll-l-2,6-benzodiazonine 1-(p-methoxyphenyl)-6-propargyl-2,3,4,5,6,7-hexahydrol H-2,6-benzodiazonine l-( p-tolyl )-6-ethyl-2,3 ,4,5,6,7-hexahydrol H-2,6- benzodiazonine 1-(3,4-dichlorophenyl)-6-methyl-4-phenyl-2,3,4,5,6,7- hexahydrol H-2,6-benodiazonine 6-benzyl-1-(3,4-dimethoxyphenyl)-2,3,4,5,6,7-hexahydrol l-l-2,6-benzodiazonine 1-(3-ch1oro-p-tolyl)-6-methyl-2,3,4,5,6,7-hexahydro- 1H-2,6-benzodiazonine 6-methyl-1-(4,5-methylenedioxyphenyl)-2,3,4,5,6,7- hexahydro-1H-2,6-benzodiazonine 6,8-dimethyll 3 ,4-methylenedioxyphenyl 2,3,4,5 ,6,7-hexahydrol l-l-2,6-benzodiazonine 1-( p-fluorophenyl )-6-methyl-2,3,4,5,6,7-hexahydro- 1H-2,6-benzodiazonine EXAMPLE 16 2-(3-hydroxypropyl)-4-p-methoxyphenyl-1-2H- phthalazinone (ll) To a flask equipped with a stirrer and Dean-Stark tube is added 46.1 g. (0.18 mole.) of 2-(4-methoxybenzoyl)-benzoic acid, 18.0 g. (0.20 mole) of 3- hydrazinopropanol and 500 ml. of toluene and the mixture refluxed with stirring until water fails to separate in the Dean-Stark tube. The solvent is then removed on a rotary evaporater and the resulting material added to 200 ml. of methanol. The mixture is then poured with stirring into water and the resulting solid filtered off and recrystallized from a mixture of toluene and pentane to obtain 2-(3-hydroxypropyl)-4-p-methoxyphenyl-1-2l-l-phthalazinone, m.p. l 17-1 18 C.

EXAMPLE 1 7 2-( 3-chloropropy1)-4-p-methoxyphenyl- 1 -2H- phthalazinone (1V) OCH:

EXAMPLE l8 5-pmethoxyphenyl-2,3,5, 1 O-tetrahydro- 1 H- pyrazol0[ 1,2-b]phthalazine (V).

OCHa

To a flask equipped with a stirring apparatus, dropping funnel, gas inlet tube and Soxhlet tube containing 45.0 g. (0.137 mole) of 2-( 3-chloropropyl)-4-pmethoxyphenyl-1-2l-l-phthalazinone is added under a nitrogen atmosphere 13.0 g. (0.34 mole) of lithium aluminum hydride and 1500 ml. of anhydrous diethyl ether. The contents of the flask are refluxed with stirring for 4 days and then cooled in an ice bath. The cooled mixture is then treated with 26 m1. of 2N sodium hydroxide and 39 m1. of water, filtered and the filtrate concentrated on a rotary evaporater. The residue EXAMPLE l9 2-( 3-hydroxypropyl 4-phenyll -2H-phthalazinone ITT-(CHMOH N To a flask equipped with a stirrer and Dean-Stark tube is added 45.2 g. (0.2 mole) of 2-benzoylbenzoic acid, 22.5 g. (0.25 mole) of 3-hydrazinopropanol, 500 ml. of toluene and L g. of p-toluenesulfonic acid and the mixture refluxed with stirring until water fails to separate in the Dean-Stark tube. The solvent is then removed on a rotary evaporater and the resulting material added to 200 ml. of methanol. The'mixture is then poured with stirring into water and the resulting solid filtered off to yield 2-( 3-hydroxpropyl)-4-phenyl- I-ZH-phthalazinone, m.p. l38139C.

EXAMPLE 2O 2-( 3-chloropropyl )-4-phenyll -2H-phthalazinone To a flask equipped with a stirrer is added 49.0 g. (0.18 mole) of 2-(3-hydroxypropyl)-4-phenyl-l-2H- phthalazinone, 25 g. (0.2 mole)(l5.2 ml.) of thionyl chloride and 250 ml. of chloroform and the mixture refluxed with stirring for 20 hours. The mixture is then treated with a cold aqueous solution of sodium bicarbonate and then washed with a saturated aqueous solution of sodium chloride. The chloroform layer is then dried with sodium sulfate, filtered and concentrated on a rotary evaporater. The resulting residue is crystallized from methylene chloride-diethyl ether-pentane to yield 2-( 3-chloropropyl)-4-phenyll -2H-phthalazinone, m.p.

EXAMPLE 21 5-phenyl-2,3 ,5 l O-tetrahydrol H-pyrazolo[ l ,2-b

I lphthalazine (V).

To a flask equipped with a stirring apparatus, dropping funnel, gas inlet tube and Soxhlet tube containing 35 g. (0.12 mole) of 2-(3-chloropropyl)-4- phenyl-l-ZH-phthalazinone is added under a nitrogen atmosphere 11.2 g. (0.3 mole) of lithium aluminum hydride-and 1500 ml. of anhydrous diethyl ether. The contents of the flask are refluxed with stirring for 48 hours and then cooled in an ice bath. The cooled mixture is then treated with 22 ml. of 2N sodium hydroxide and 34 ml. of water, filtered and the filtrate concen trated on a rotary evaporater to yield S-phenyl- 2,3,5,l0-tetrahydro-lH-pyrazolo[ l ,2,-b]phthalazine as an oil. The oil is dissolved in anhydrous diethyl ether and the resulting solution cooled in an ice bath.

Hydrogen chloride gas is then passed through the cooled solution and the solids which form filtered off and dried to yield 5-phenyl-2,3,5,IO-tetrahydro-IH- pyrazolo[l,2-b]phthalazin hydrochloride, -m.p. l97-l99 C. 7

What is claimed is:

l. A compound of the formula wherein R represents hydrogen, lower alkyl, cyclolower alkyl or phenyl;

R, R" and R' each independently represent hydrogen, chlorine or straight chain lower alkyl;

R, R and R each independently represent hydrogen, chlorine, fluorine, straight chain lower alkyl, straight chain lower alkoxy; or R together with either R or R form a methylenedioxy bridge; and

A represents chlorine or hydroxyl.

2. The compound of claim 1 which is 2-(3-hydroxypropyl )-4-p-chlorophenyll -2H-phthalazinone.

3. The compound of claim 1 which is 2( 3- chloropropyl )-4-p-chlorophenyll -2H-phthalazinone.

4. The compound of claim 1 which is 2-(3-hydroxypropyl)-4-p-methoxyphenyl-I-ZH-phthalazinone.

5. The compound of claim 1 which is 2-(3- chloropropyl )-4-p-methoxyphenyl- 1 -2H- phthalazinone.

6. The compound of claim 1 which is 2-(3-hydroxypropyl )-4-phenyll -2l-l-phthalazinone.

7. The compound of claim 1 which is 2-(3- chloropropyl )-4-phenyl- 1 -2H-phthalazinone.

8. A compound of the formula IfIH N-CHzCHRCHsOH Riv Rvi R! R VI I\%-R wherein R represents hydrogen, lower alkyl, cyclolower alkyl or phenyl;

R, R" and R' each represent hydrogen, chlorine or straight chain lower alkyl; and

R, R and R" each independently represent hydrogen chlorine, fluorine, straight chain lower alkyl, straight chain lower alkoxy, or R" together with either R or R form a methylenedioxy bridge.

11. A pharmaceutically acceptable acid addition salt iz ."lfi iifiin'il 3? claim 10 which is 5-pchlorophenyl-2,3,5, IO-tetrahydrol H-pyrazolol l ,2-b] phthalazine.

13. The compound of claim 10 which is S-phenyl- 2,3,5,]0-tetrahydro-1H-pyrazolo[ l,2-b]phthalazinc.

14. The compound of claim 10 which is S-p-mcthoxyphenyl-2,3,5, l O-tetrahydrol H-pyrazolol 1,2-b] phthalazine.

15. An N -R halide salt of a compound of claim 10 wherein R represents straight chain lower alkyl, ally], propargyl or benzyl and the halide moiety is a halogen having an atomic weight of at least 35.

16. The compound of claim 15 which is N -methyl iodide salt of 5-p-chlorophenyl-2,3,5,lO-tetrahydro-l H-pyrazolo[ l,2-b]phthalazine.

17. A process for preparing the compounds of claim 10 which comprises treating a compound of the formula:

Riv Rvl where R, R, R", R, R, R and R' are defined in claim 10 with a hydride reducing agent.

18. A process of claim 1 wherein the hydride reducing agent is an aluminum hydride.

19. A process of claim 17 wherein the hydride reducing agent is lithium aluminum hydride.

UNITED STATES PATENT @FFEQE cr rrFicAr-E or CQRREQTWN Patent 15. 3,694,442 Dated September 26, 1972 Inventor(s) 1 WILLIAM J. HO UI LIHAN It is certified that error appears in the above-identified, patent and that said Letters Patent are hereby corrected as shown below:

Assignee:- SANDOZ -WANDER, INC.

Q Hanover, New Jersey Column 3 line 63 delete the word "bnrlzoyl" I and insert the word :benzoyl--. 7 Column 19 line. 27 delete the word "tetrahydrophthalazinne" and in sert the'word v I tetrahydrophth ala zine--.

Column 20 line delete the number "1" and insert the number -17- Signed and sealedtnis ZSth day of December 1973.

(SEAL) Attest:

EDWARD M. FLETCHER,JR. RENE D. TEGTMEYER Attesting Officer- I Acting Commissioner of Patents FORM PO-105O (1069) 

2. The compound of claim 1 which is 2-(3-hydroxypropyl)-4-p-chlorophenyl-1-2H-phthalazinone.
 3. The compound of claim 1 which is 2-(3-chloropropyl)-4-p-chlorophenyl-1-2H-phthalazinone.
 4. The compound of claim 1 which is 2-(3-hydroxypropyl)-4-p-methoxyphenyl-1-2H-phthalazinone.
 5. The compound of claim 1 which is 2-(3-chloropropyl)-4-p-methoxyphenyl-1-2H-phthalazinone.
 6. The compound of claim 1 which is 2-(3-hydroxypropyl)-4-phenyl-1-2H-phthalazinone.
 7. The compound of claim 1 which is 2-(3-chloropropyl)-4-phenyl-1-2H-phthalazinone.
 8. A compound of the formula
 9. The compound of claim 8 which is 1-p-chlorophenyl-3-(3-hydroxypropyl)-1,2,3,4-tetrahydrophthalazinne.
 10. A compound of the formula
 11. A pharmaceutically acceptable acid addition salt of a compound of claim
 10. 12. The compound of claim 10 which is 5-p-chlorophenyl-2,3,5,10-tetrahydro-1H-pyrazolo(1,2-b)phthalazine.
 13. The compound of claim 10 which is 5-phenyl-2,3,5,10-tetrahydro-1H-pyrazolo(1,2-b)phthalazine.
 14. The compound of claim 10 which is 5-p-methoxyphenyl-2,3,5, 10-tetrahydro-1H-pyrazolo(1,2-b)phthalazine.
 15. An N11-Rvii halide salt of a compound of claim 10 wherein Rvii represents straight chain lower alkyl, allyl, propargyl or benzyl and the halide moiety is a halogen having an atomic weight of at least
 35. 16. The compound of claim 15 which is N11-methyl iodide salt of 5-p-chlorophenyl-2,3,5,10-tetrahydro-1H-pyrazolo(1,2-b)phthalazine.
 17. A process for preparing the compounds of claim 10 which comprises treating a compound of the formula:
 18. A process of claim 1 wherein the hydride reducing agent is an aluminum hydride.
 19. A process of claim 17 wherein the hydride reducing agent is lithium aluminum hydride. 